This Program Project Grant application has been initiated to develop a team approach to clarify the mechanisms by which local factors regulate bone remodeling, and in particular osteoclastic bone resorption. It is our hypothesis that bone remodeling is mediated by local factors generated in the bone and bone marrow microenvironment, and that osteoporosis results from abnormalities in the interactions between these local factors and bone cells. Recent studies by ourselves and others indicate that these local factors are heterogeneous, and the complete characterization of their effects on bone cells will require a broadly-based approach involving investigators with expertise in widely disparate but related areas. The specific aims of this application are: 1. To identify the specific cellular and molecular events involved in normal osteoclastic bone resorption, including a) the signaling mechanisms involved in osteoclast activation; b) the expression of proteins related to osteoclast differentiation and bone resorption; c) the activation of TGF beta during resorption, and its regulation; 2. To determine how these cellular and molecular mechanisms are disordered in Paget's disease. We plan to use the rapidly expanding techniques of bone cell biology, protein chemistry and molecular biology to clarify the mechanisms by which these local factors interact with bone cells. Since the expertise required to identify and characterize these various mechanisms will require the attention of investigators with different types of skills, a team approach will be used to unite a number of diverse approaches around the tightly focused goal of clarifying the mechanisms by which local factors regulate normal and abnormal bone remodeling.